Increased solubility flavanolignan preparations

ABSTRACT

The inventors have devised novel approaches for the preparation of flavanolignan compositions of enhanced solubility and substantially free of toxic contaminants. Such novel approaches are based on spray drying or lyophilizing to dry a diluted preparation of flavanolignan. These approaches avoid the use of toxic excipients and or carriers commonly used to precipitate flavanolignan concentrates and thus address the drawbacks of existing methods and compositions.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention relates to compositions and a process for the manufactureof a flavanolignan-containing substance from milk thistle displayingenhanced aqueous solubility relative to pure flavanolignan preparations.The substance of the method according to the invention is useful for themanufacture of solid medicinal products and dietary supplements withdesired improved dissolution characteristics.

2. Summary of the Related Art

Fruits of milk thistle (Silybum marianum (L.) Gaertn.) contain severalisomeric compounds of flavanol-lignane type of the general formulaC₂₅H₂₂O₁₁-silybinin A, silybinin B, isosilybinin A, isosilybinin B,silydianin and silychristin—collectively called flavanolignans of milkthistle or silymarin. Silymarin (generally available as the dry extractof milk thistle) has been reported to have numerous pharmacologicalactivities such as for example, antioxidant effect, stabilization ofcell membranes, and stimulation of biosynthesis of proteins to mention afew. Silybin (a mixture of silybinin A and silybinin B) has been foundto be particularly suited as an hepatoprotective agent. Silymalin iseffective in the treatment and prophylaxis of liver disease includingacute and chronic intoxication of the liver caused by toxins, (includingdrugs and various alcohols, e.g., carbon tetrachloride, galactosamine,paracetamol, ethanol, phalloidin and α-amanitin). Silymarin is an activecomponent of pharmaceutical products, (e.g., LEGALON®, Madus AG, Koln,Germany; Hepamarin, Pharmasan GmbH, Freiburg, Germany; HEPADURAN®,Zwinkscher GmbH, Karlsruhe, Germany; or SILYHEXAL®, Hexal Pharma AG,Wien, Austria) used to treat and prevent hepatic diseases. Moreinformation about silymarin and its use can be found in Morazzoni etal., Fitoterapia, LXVI, 3-42, (1995); Sailer et al., Drugs, 61:2035-2063, (2001); Wellington et al., BioDrugs, 15(7): 465-489, (2001).

The silymarin preparation used for manufacture of pharmaceuticalpreparations or food supplements is thus a purified extract standardizedto include specific flavanolignans. Pharm. Forum 28: 418-420, (2002)provides that silymarin contains not less than 90% and not more than110% of silymarin, calculated as silybin on the dried basis; consistingof not less than 20.0% and not more than 45.0% of the sum of silydianinand silycristin; not less than 40% and not more than 65% for the sum ofsilibin A and silibin B; and not less 10.0% and not more than 20% forthe sum of isosilybin A and isosilybin B; contains from about 40 up to80% flavanolignans consisting of from about 40 up to 65% of the sum ofsilybinin A and B; from about 20 up to 45% of the sum of silychristinand silydianin and from about 10 up to 20% of the sum of isosilybinin Aand B.

However, the use of milk thistle flavanolignans in general and that ofsilymarin and its components in the preparation of pharmaceuticalproducts is greatly impaired by the low solubility in both hydrophilicand lipophilic environments of these compounds which greatly reducestheir bioavailability and resorbability in mammals. Given the tremendoustherapeutic potential, it is not surprising that several investigatorshave sought a variety of approaches to address thesolubility/bioavailability problems as attested by the large body ofliterature on point including several patents discussed hereinafter.

One approach lies in the preparation of silybin esters (mixture ofsilybinins A and B, possibly also isosilybinins A and B) withdicarboxylic acid. For example U.S. Pat. Nos. 4,895,839 and 5,196,448describe a di-sodium salt of bis-hemisuccinate of silybin. Thispreparation is presently incorporated in in LEGALON® SIL inj., apharmaceutical product for the treatment of serious poisoning by Amanitamushrooms or other hepatotoxic compounds, marketed by Madaus &Co.

Another approach has been the preparation of silybin glycosides as setforth for example in CZ Patent No. 287 657. The described silybinglycosides are more soluble in water than silybin and they show similareffects as silymarin. Complex compounds of silymarin or silybin withphospholipides are also described by U.S. Pat. Nos. 4,764,508 and4,895,839. These complexes are prepared by dissolution of components (1mol of silymarin or silybin and 0.3 up to 2.0 mol of phosphatidylcholine, phosphatidyl serine or phosphatidyl ethanolamine) in aproticsolvent (dioxane or acetone) and by precipitation of the complex byaddition of aliphatic hydrocarbon or lyophilization or spray drying. Thedescribed complex compounds are the basis of the substance calledSILIPED™ or SILYPHOS™, (manufactured by Indena) currently under clinicaltrials (Comoglio A., et al., Biochem. Pharmacol., 50:(8):1313-1316(1995).

Yet another approach has been formulation in cyclodextrin complexesnotorious for their role in solubilizing a variety of compounds.Inclusion complexes of silybinin with cyclodextrines are described inthe U.S. Pat. No. 5,198,430. Complexes of silybinin are described withα-, β- and γ-cyclodextrine and their derivatives in molecular ratio of 1mol of silybinin with 1 up to 4 mol of the corresponding cyclodextrine.Complexes are prepared by dissolution of both components in aqueousammonia and by removal of the ammonia either by evaporation orneutralization with hydrochloric acid and by subsequent drying orlyophilization.

Solutions of silymarin in polyethylene glycol alone or in polyethyleneglycol and some co-solvents and/or surfactants are described in WO99/18985. The gelatin capsules filled with such solutions show highersolubility in dissolution tests than silymarin alone.

Another patented procedure for increasing the biological availability ofsilymarin consists in the preparation of coprecipitates offlavanolignans with carriers and detergents (see for example, U.S. Pat.No. 5,906,991 and EP 722719). Suitable carriers according to thesemethods include water soluble saccharides, derivatives of cellulose andpolyvinylpyrrolidone whereas polysorbates of fatty acids are used asdetergent. These coprecipitates are said to have higher solubilityproperties as compared to untreated silymarin. However, some of theseobligatory carriers and excipients according to these patentscoprecipitate as contaminants with the flavanolignans. Unfortunately,some of these contaminants are known toxic compounds and thus mayproduce adverse reactions in a patient further exacerbating an alreadyexisting condition.

Thus, the currently available approaches for the preparation offlavanolignan compositions suffer from a number of drawbacks. Ingeneral, conventional methodologies fail to produce a sufficientlysoluble preparation. Moreover, because of the low solubility, suchpreparations are not sufficiently bioavailable. A further disadvantageof the formulations in presently the art is that often the flavanolignanis bound to a chemical compound which can physiologically act as aforeign substance in the body thereby bringing about undesired sidereactions or impair the effectiveness of the flavanolignan. Therefore,there remains a need to identify and develop improved methodologies andcompositions. Such methodologies and compositions should overcome theshortcomings of the traditional methods in the literature. It is anobject of the present invention to provide flavanolignan preparationswhich reduce the binding of the flavanolignans to foreign compounds andpossess high rate of liberation wherein the liberation is accomplishedphysically by means of destruction of its crystalline lattice (amorphoussubstance). These flavanoligaans preparations should maintain theirefficacy while limiting their binding to foreign compounds.

SUMMARY OF THE INVENTION

The inventors have devised novel approaches for the preparation offlavanolignan compositions of enhanced solubility and substantially freeof toxic contaminants. Such novel approaches are based on spray dryingor lyophilizing to dry a diluted preparation of flavanolignan. Theseapproaches avoid the use of toxic excipients and or carriers commonlyused to precipitate flavanolignan concentrates and thus address thedrawbacks of existing methods and compositions.

The process achieves this advantage through the use of non-toxicwater-soluble compounds and spray drying or lyophilizing techniquesselected and applied to produce an amorphous product shown to havegreater solubility in an aqueous environment. The compositions of theinstant invention achieve greater solubility (and thus higherbioavailability) without the need of materials such as wetting agents,or the use of materials such as complexing agents with physiologicalactivity that could result in undesired side reactions or impair theeffectiveness of the flavanolignin product.

The patents and scientific literature referred to herein establish theknowledge of those with skill in the art and are hereby incorporated byreference in their entirety to the same extent as if each wasspecifically and individually indicated to be incorporated by reference.Any conflict between any reference cited herein and the specificteachings of this specification shall be resolved in favour of thelatter. Likewise, any conflict between an art-understood definition of aword or phrase and a definition of the word or phrase as specificallytaught in this specification shall be resolved in favour of the latter.

In one aspect, the invention relates to methods for the preparation of aflavanolignan composition by preparing a solution of an organic solutionof one or more flavanolignans, and at least one water-soluble compound,and spray drying or lyophilizing the solution to obtain an amorphousproduct. In another aspect, the invention provides a dry, amorphousco-precipitate of one or more flavanolignan and at least one sugaralcohol.

These and other features of the invention will be further described andexemplified in the detailed description below.

DETAILED DESCRIPTION OF THE INVENTION

It has now been found, and it constitutes on object of the presentinvention that the use of spray drying or lyophilizing to prepareflavanolignan compositions results in preparations well suited forpharmacological and nutraceutical uses. The methods and compositionsdisclosed herein capitalize on the discovery providing much neededpreparations which are soluble in a aqueous environment and which aresubstantially free of potentially toxic contaminants.

Technical and scientific terms used herein have the meaning commonlyunderstood by one of skill in the art to which the present inventionpertains, unless otherwise defined. Reference is made herein to variousmethodologies and materials known to those of skill in the art. Standardreference works setting forth the general principles of pharmacologyinclude Goodman and Gilman's The Pharmacological Basis of Therapeutics10^(th) Ed., McGraw Hill Companies Inc., New York (2001). Any suitablematerials and/or methods known to those of skill can be utilized incarrying out the present invention. However, preferred materials andmethods are described. Materials, reagents and the like to whichreference is made in the following description and examples areobtainable from commercial sources, unless otherwise noted.

Reference is made hereinafter in detail to specific embodiments of theinvention. While the invention will be described in conjunction withthese specific embodiments, it will be understood that it is notintended to limit the invention to such specific embodiments. On thecontrary, it is intended to cover alternatives, modifications, andequivalents as may be included within the spirit and scope of theinvention as defined by the appended claims. In the followingdescription, numerous specific details ate set forth in order to providea thorough understanding of the present invention. The present inventionmay be practiced without some or all of these specific details. In otherinstances, well known process operations have not been described indetail in order not to unnecessarily obscure the present invention.

The methods of the present invention are intended for use with anymammal which may experience the benefits of the methods of theinvention. Foremost among such effectiveness, although the invention isnot intended to be so limited, and is applicable to veterinary uses.Thus, in accordance with the invention, “mammals” include humans as wellas non-human mammals, particularly domesticated animals including,without limitation, horses, cows, sheep, dogs, cats, goats, reindeer,and elephants.

It will be understood that the mammal to which a compound of theinvention is administered need not suffer from a specific disease state.Indeed, the compounds of the invention may be administeredprophylacticly, prior to any development of symptoms. The term“therapeutic,” “therapeutically,” and permutations of these terms areused to encompass therapeutic, palliative as well as prophilactic uses.Hence, as used herein, by “treating or alleviating the symptoms” ismeant reducing, preventing, and/or reversing the symptoms of theindividual to which a compound of the invention has been administered,as compared to the symptoms of an individual receiving no suchadministration.

Surprisingly, it has been found that the solubility of flavanolignans(such as silymarin exemplified hereinafter) is improved as compared toconventional preparations by spray drying or lyophilizing a solution ofan organic solution of one or more flavanolignans, and at least onewater-soluble compound to obtain an amorphous product. X-ray powderdiffraction analysis has shown that soluble flavanolignans preparationstend to be amorphous whereas poorly soluble ones are crystalline innature. Formulations obtained according to the methods of the inventionare preferably a dry-powder form of an amorphous product suitable forpharmacological and nutraceutical uses. Especially preferredflavanolignans according to the invention include silybin, silydianin orsilymarin.

An amorphous product prepared by spray drying or by lyophilizing asolution of a flavanolignan (e.g., silymarin) in ethanol, acetone,methanol, isopropylalcohol or ethyl acetate has very low bulk densityand is difficult to use. The inventors have discovered that the additionof a water soluble compound, dissolved in water, to an organic solutionof one or more flavanolignans (e.g., water-ethanol, water-acetone,water-methanol or water-isopropyl alcohol solutions of silymarin) priorto spray drying or lyophilizing inhibits crystallization therebyproducing an amorphous product having the desired solubility propertiesas discussed above. The addition of a water soluble compound to anorganic solution of one or more flavanolignans is postulated tocontribute to the higher solubility observed by creating a water-solublematrix facilitating access of water to the amorphous flavanolignans.Accordingly, one or more flavanolignans are substantially dissolved inan organic solvent and the organic solution is mixed with an aqueoussolution containing one or more water-soluble compounds.

In some embodiments of the invention, the flavanolignans solution usedfor the spray drying comprises about 10 weight parts of one or moreflavanolignans dissolved in 30-120 weight parts organic solvent(hereinafter “organic solution”). An aqueous solution containing fromabout 0.5-10 weight parts of at least one water-soluble compound(hereinafter “aqueous solution”) is prepared. The organic solution andaqueous solution are then mixed so that the ratio of flavanolignans andwater soluble compounds in the final dry product is in the range of 10:0.5-10.

Organic solvents according to the invention are non-branched andbranched alkanols or ketones having 1-4 carbon atoms, including forexample, ethanol, methanol, isopropyl alcohol, water-tert. butanol,acetone, or mixtures thereof.

The inventors have also discovered that flavanolignans' crystallizationfrom the organic-aqueous solution (e.g., water-ethanol, water-acetone,water-methanol or water-isopropylalcohol solution of silymarin) can bereduced by the addition of water-soluble compounds. Contemplatedwater-soluble compounds include sugar alcohols such as for example,tetritols, pentitols or hexitols (e.g., mannitol, treitol, erytritol,arabinitol, xylitol, talitol, maltitol or sorbitol).

Flavanolignans' compositions (e.g., silybin, silydianin or silymarin)according to the invention will include an amorphous co-precipitateconsisting essentially of one or more flavanolignan, and at least onesugar alcohol. In some compositions the alcohol is a tetritol, pentitolor a hexitol. Formulations according to the invention include anycomposition obtained according to the methods and materials as discussedabove.

The methods of the invention do not rely on wetting agents or oncomplexing agents which may give rise to undesired side reactions orimpair the effectiveness of the ultimate flavanolignin-containingproduct.

The solubility (and possibly the biological availability) of purifiedcomponents of silymarin, silybin (mixture of silybinin A and silybininB) or silydianin in water is negligible due to their crystalline:structure. Traditionally these purified compounds are not consideredamenable for pharmacological and nutraceutical uses. One of skill willappreciate that it is possible to exploit the present discoveries forthe preparation of these purified components where the danger ofcrystallization in the course of drying is known to be substantiallyhigher than that of flavanolignans solutions.

From a practical standpoint, higher concentrations of inactivecomponents are not desirable for pharmacological and nutraceutical usesinsofar as it results in an overall reduced amount of active ingredientson a weight by weight basis. One of skill will realize that an importantadvantage of the invention lies in the fact that higher solubility isrealised by addition of only a relatively small quantity of non-toxicinactive ingredients.

It has been found experimentally that in order to increase thesolubility of the solution of flavanolignans, it suffices to add 5% w/wof the final product of the water soluble compounds (e.g., the sugaralcohol described herein). On the other hand, in order to increasesolubility of pure flavanolignans (e.g., silybin and silydianin), it isnecessary to use higher concentrations of the water soluble compounds(usually at least 30% w/w).

Compositions containing therapeutically effective amounts of the anymilk thistle extract prepared according to the invention are useful forthe treatment of any mammal affected by any condition responsive toflavanolignan treatment (e.g., diabetes, colon cancer, hypoglycaemia seefor example: Marles et al., Phytomedicine 2:137-189, (1995) and Soto etal., Clin. Pharmacology, Toxicology & Endocrinology, 119:125-129,(1998)). Recently, the use of flavanolignans from milk thistle has alsobeen patented as adjuvants in tumour chemotherapy (U.S. Pat. No.5,714,473) as well as antiproliferative medicines (U.S. Pat. No.5,912,265).

Additionally, flavanolignans compositions according to the invention maybe incorporated in a food supplement such as in nutraceuticals alone orin combination with other active ingredients. For example,flavanolignans compositions may be combined with synergistically actinginsoluble fibres from the plant of the family Amaranthus and with animalchitosan a well as with soluble fibre from the seeds of Cyamopsistetragonoglobulus (galactomanan guar).

The compositions of the present invention may be provided in apharmaceutically acceptable vehicle using formulation methods known tothose of ordinary skill in the art. The compositions of the inventioncan be administered by standard routes. The compositions of theinvention include those suitable for oral, inhalation, rectal,ophthalmic (including intravitreal or intracameral), nasal, topical(including buccal and sublingual), vaginal, or parenteral (includingsubcutaneous, intramuscular, intravenous, intradermal, andintratracheal). In addition, polymers may be added according to standardmethodologies m the art for sustained release of a given compound.

The formulations of the compositions of the invention may convenientlybe presented in unit dosage form and may be prepared by conventionalpharmaceutical techniques as discussed above. Such techniques includethe step of bringing into association the compound of the invention andthe pharmaceutically acceptable carrier(s), such as a diluent or anexcipient. In general, the formulations are prepared by uniformly andintimately bringing into association the active ingredient with liquidcarriers or finely divided solid carriers or both, and then, ifnecessary, shaping the product.

Pharmaceutical compositions comprising the compounds of all of theaspects of the present invention suitable for oral administration may bepresented as discrete units such as capsules, caplets, gelcaps, cachets,pills, or tablets each containing a predetermined amount of the activeingredient as a powder or granules; as a solution or a suspension in anaqueous liquid or a non-aqueous liquid; or as an oil-in-water liquidemulsion or a water-in-oil emulsion and as a bolus, etc. Alternately,administration of a composition of all of the aspects of the presentinvention may be effected by liquid solutions, suspensions or elixirs,powders, lozenges, micronized particles and osmotic delivery systems.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared bycompressing, in a suitable machine, the active ingredient in afree-flowing form such as a powder or granules, optionally mixed with abinder, lubricant, inert diluent, preservative, surface active ordispersing agent. Molded tablets may be made by molding, in a suitablemachine, a mixture of the powdered compound moistened with an inertliquid diluent. The tablets may be optionally coated or scored and maybe formulated so as to provide a slow or controlled release of theactive ingredient therein.

Dosages will depend on the condition being treated, the particularcompound of the invention being adminstered, and other clinical factorssuch as age, weight and condition of the mammal and the route ofadministration.

The term “therapeutically effective amount” is used to denote treatmentsat dosages effective to achieve the therapeutic result sought.Furthermore, one of skill will appreciate that the therapeuticallyeffective amount of the compound of the invention may be lowered orincreased by fine tuning and/or by administering more than one compoundof the invention, or by administering a compound of the invention withother therapeutic modalities. The invention therefore provides a methodto tailor the administration/treatment to the particular exigenciesspecific to a given mammal. Therapeutically effective amounts may beeasily determined for example empirically by starting at relatively lowamounts and by step-wise increments with concurrent evaluation ofbeneficial effect.

The following examples are intended to further illustrate certainpreferred embodiments of the invention and are not limiting in nature.Those skilled in the art will recognize, or be able to ascertain, usingno more than routine experimentation, numerous equivalents to thespecific substances and procedures described herein. Such equivalentsare considered to be within the scope of this invention, and are coveredby the following claims.

EXAMPLES

The starting silymarin in Example 1 had from about 40 up to 80%flavanolignans out of which from about 40 up to 65% was silybinin, about10 up to 20% isosilybinin and about 20 up to 45% silydianin andsilychristin.

Example 1 Preparation of Representative Flavanolignans CompositionsContaining Silymarin

Sample 1

80 gms of silymarin were dissolved in 600 ml of absolute ethanol underboiling conditions. 20 gms mannitol were dissolved in 200 ml of water bystirring. The mannitol solution was heated and subsequently added to thesilymarin solution by stirring. The solution obtained was kept at theminimum temperature of 75° C. and was gradually spray dried in thestream of hot nitrogen (130-135° C.) on a Buchi Spray Dryer to asubstantially dry product.

Sample 2

95 gms of silymarin were dissolved in 600 ml of acetone under boilingconditions. A hot solution of 5 gms sorbitol in 100 ml of water wasadded to the silymarin solution by stirring. The solution obtained waskept under reflux and was gradually spray-dried (the dryer andconditions as in Sample 1) to obtain a substantially dry product.

Sample 3

90 gms of silymarin were dissolved in 900 ml of methanol under boiling.A hot solution of 10 gms mannitol in 100 ml of water was added to thesilymarin solution by stirring. The solution obtained was kept underreflux and was gradually spray-dried (the dryer and conditions as inSample 1) to obtain a substantially dry product.

Sample 4

85 gms of silymarin were dissolved in 900 ml of isopropylalcohol underboiling. Hot solution of 15 gms xylitol in 100 ml of water was added tothe silymarin solution by stirring. The solution obtained was kept atthe minimum temperature of 80° C. and was gradually spray-dried (thedryer and conditions as in Sample 1) to a substantially dry product.

Dissolution Tests

To illustrate the desirable characteristics of the flavanolignanscompositions of the invention, samples 1 to 4 and the initial silymarinpreparation were compared as to their relative solubility byconventional dissolution testing. For this purpose 100 mg of eachSamples were filled in hard gelatin capsules (number 00). Individualcapsules underwent the test on the device as per the Ph. Eur. Type 2 in2 litres of the dissolution medium pH 7.5 and under 100 revolutions perminute. Table 1 gives mathematical average values computed from thedissolution of 6 capsules after 30 and 60 minutes.

TABLE 1 Dissolution Values Sample 30 minutes 60 minutes Silymarin 41.3%45.9% Sample 1 82.5% 88.1% Sample 2 77.8% 83.0% Sample 3 79.4% 81.5%Sample 4 83.4% 85.8%

Example 2 Preparation of Additional Representative FlavanolignansCompositions From Pure Flavanolignans

Sample 1

30 gms of silybin were dissolved in 450 ml of ethanol and heated toboiling. A hot solution of 10 gms sorbitol in 100 ml of water was addedto the silybin solution. The solution obtained was kept at the minimumtemperature of 75° C. and was gradually dried (the dryer and conditionsas in Example 1) on spray dryer to a substantially dry product.

Sample 2

30 gms of silybin were dissolved in 450 ml of ethanol and heated toboiling. A hot solution of 20 gms sorbitol in 100 ml of water was addedto the silybin solution. The solution obtained was kept at the minimumtemperature of 75° C. and was gradually dried (the dryer and conditionsas in Example 1) on spray dryer to a substantially dry product.

Sample 3

30 gms of silybin were dissolved in 450 ml of ethanol and heated toboiling. A hot solution of 30 gms sorbitol in 100 ml of water was addedto the silybin solution. The solution obtained was kept at the minimumtemperature of 75° C. and was gradually dried (the dryer and conditionsas in Example 1) on spray dryer to a substantially dry product.

Sample 4

30 gms of silybin were dissolved in 450 ml of ethanol and heated toboiling. A hot solution of 10 gms manitol in 100 ml of water was addedto the silybin solution. The solution obtained was kept at the minimumtemperature of 75° C. and was gradually dried (the dryer and conditionsas in Example 1) on spray dryer to a substantially dry product.

Sample 5

30 gms of silydianin were dissolved in 350 ml of ethanol and heated toboiling. A hot solution of 10 gms sorbitol in 100 ml of water was addedto the silydianin solution. The solution obtained was kept at theminimum temperature of 75° C. and was gradually dried (the dryer andconditions as in Example 1) on spray dryer to a substantially dryproduct.

Dissolution Tests

Samples 1 to 5 and the initial silybin preparation were tested byconventional dissolution testing as described for Example 1 above. Thedata are presented in Table 2 below.

TABLE 2 Dissolution Values Sample 30 minutes 60 minutes Silybin 4.6%4.5% Sample 1. 85.5% 84.1% Sample 2. 79.3% 83.0% Sample 3. 82.2% 81.7%Sample 4 87.3% 85.1% Sample 5 89.0% 84.5%

Example 3 Preparation of Representative Pharmaceutical Formulations

This example illustrates the preparation of representative hard gelatincapsules comprising flavanolignans compositions according to theinvention (e.g., 140 mg of silymarin (as measured by HPLC)).

Amounts provided for 1000 capsules are as follows: Powdered extract frommilk thistle (as per the example 1, 255.00 g sample 1) Micro-crystallinecellulose (Avicel PH 302)  45.00 g Talc  9.00 g Magnesium stearate  3.00g 0.312 g of the homogeneous mixture are filled per capsule.

Example 4 Preparation of Representative Nutraceutical Formulations

The instant example illustrates the preparation of representativenutraceutical compositions containing flavanolignans according to theinvention. An 8 gms silymarin granulate dose with vegetable fibres isexemplified.

Powdered extract from milk thistle 0.5000 g Galactomanan guar 2.0000 gAmaranthine fibres 2.0000 g Chitosan 2.0000 g L-Carnitine tartarate0.7360 g Acesulfam potassium salt 0.0640 g Mannitol up to 8.0000 g

The mixture of powders formed by the extract from milk thistle,galactomanan guar, amaranthine fibres and chitosan is granulated with anaqueous solution of L-carnitine tartarate, acesulfam potassium salt andmannitol.

1. A method for the preparation of a flavanolignan composition,comprising the steps of: (a) providing a solution comprising an organicsolution of one or more flavanolignans substantially dissolved in anorganic solvent and at least one water-soluble compound, wherein saidsolution does not comprise a wetting agent or a complexing agent; and(b) drying the solution of step (a) to obtain a product which does notcomprise a wetting agent or a complexing agent; wherein the drying isspray drying or lyophilization.
 2. The method of claim 1, wherein thesolution is dried by spray drying.
 3. The method of claim 1, wherein theproduct is an amorphous product.
 4. The method of claim 1, wherein step(a) of providing the solution comprises mixing said organic solutioncomprising said one or more flavanolignans with an aqueous solutioncomprising said at least one water-soluble compound.
 5. The method ofclaim 4, wherein the water-soluble compound is a sugar alcohol.
 6. Themethod of claim 4, wherein the sugar alcohol is selected from the groupconsisting of tetritols, pentitols and hexitols.
 7. The method of claim4, wherein the sugar alcohol is selected from the group consisting ofxylitol, mannitol, and sorbitol.
 8. The method of claim 4, wherein thesolution comprises about 10 weight parts of the organic solution of oneor more flavanolignans substantially dissolved in 30-120 weight partsorganic solvent mixed with an aqueous solution containing about 0.5-10weight parts of at least one water-soluble compound, wherein the ratioof flavanolignans and water soluble compounds in the final dry productis in the range of 10:0.5-10.
 9. The method of claim 4, wherein theorganic solvent is selected from the group consisting of non-branchedalkanols, branched alkanols, and ketones, each having 1-4 carbon atoms.10. The method of claim 4, wherein the organic solvent is selected fromthe group consisting of ethanol, methanol, isopropylalcohol,water-tert-butanol, and acetone, or a mixture thereof.
 11. The method ofclaim 4, wherein the one or more flavanolignans comprise silybin,silydianin or silymarin.
 12. A flavanolignan composition, consistingessentially of a dry, amorphous co-precipitate consisting essentially ofone or more flavanolignans and at least one sugar alcohol, wherein eachsaid flavanolignan is a compound of flavanol-lignane type having thegeneral formula C₂₅H₂₂O₁₁.
 13. The composition of claim 12, wherein thesugar alcohol is selected from the group consisting of tetritol,pentitol and hexitol.
 14. The composition of claim 12, wherein each ofthe one or more flavanolignans is silybin, silydianin or silymarin. 15.A flavanolignan composition prepared according to the method of claim 1,wherein each said flavanolignan is a compound of flavanol-lignane typehaving the general formula C₂₅H₂₂O₁₁.
 16. A dry, amorphousco-precipitate consisting essentially of (i) one or more flavanolignans,and (ii) one or more sugar alcohols, wherein each said flavanolignan isa compound of flavanol-lignane type having the general formulaC₂₅H₂₂O11.
 17. The co-precipitate of claim 16, wherein each said sugaralcohol is selected from the group consisting of tetritol, pentitol andhexitol.
 18. The co-precipitate of claim 16, wherein each saidflavanolignan is silybin, silydianin or silymarin.
 19. The compositionof claim 14, wherein the one or more flavanolignans comprise silymarin,and wherein the sugar alcohol is mannitol.
 20. The composition of claim19, wherein the composition comprises 5% of said mannitol on a weight byweight basis.
 21. The composition of claim 18, wherein the one or moreflavanolignans comprise silymarin, and wherein the sugar alcohol ismannitol.
 22. The composition of claim 21, wherein the compositioncomprises 5% of said mannitol on a weight by weight basis.
 23. Themethod of claim 1, wherein the one or more flavanolignans comprisesilymarin, wherein the water-soluble compound is mannitol, and whereinthe organic solution is ethanol solution.
 24. A flavanolignancomposition prepared according to the method of claim 23.